Neurofibromatosis type 2 is an inherited disorder characterized by the development of Schwann cell tumors of the eighth cranial (auditory) nerve. Mutations and loss of heterozygosity of the NF2 locus have been detected in various familial and sporadic tumors of the nervous system, including schwannomas, meningiomas, and ependymomas. These mutations have been detected both in the germ-line of Nf2 patients and sporadically occurring tumors, indicative of a classical tumor suppressor gene pattern. Together, these tumors account for approximately 30% of central nervous system neoplasms in adults. In further support of a role for NF2 in tumor suppression, mice heterozygous for a Nf2 mutation are predisposed to a wide variety of tumors with high metastatic potential. In a separate model in which Nf2 was inactivated specifically in Schwann cells, mice developed schwannomas and Schwann cell hyperplasia.
The longest and predominant splice form of the Nf2 gene codes for a 595-amino acid protein called merlin that is highly similar to the band 4.1 family of proteins. It is most closely related to the ERM proteins—ezrin, radixin, and moesin. The ERM proteins are thought to function as cell membrane-cytoskeleton linkers and are localized to cortical actin structures near the plasma membrane such as microvilli, membrane ruffles, and lamellipodia. Likewise, merlin is localized to cortical actin structures in patterns that partially overlap with the ERMs. It has been proposed that intramolecular binding of the N-terminal and C-terminal domains conformationally regulates the ERM proteins by masking binding sites for interacting proteins. The ERMs can also form homo-dimers and hetero-dimers among themselves and with merlin, adding an additional level of complexity to the regulation of these proteins. The recently solved crystal structure of moesin N/C-terminal complex strengthens this model of conformational regulation.
Unfortunately, many of the current treatments that destroy cancerous cells also affect normal cells, resulting in a variety of possible side-effects, such as nausea, vomiting, low blood cell counts, increased risk of infection, hair loss, and ulcers in mucous membranes. Thus, improved methods are needed for the treatment and prevention of cancers, such as cancers of the nervous system.